Mechanisms of thymic stromal-immune crosstalk for homeostasis and naïve T cell licensing across life

胸腺基质-免疫串扰在生命过程中维持稳态和幼稚 T 细胞许可的机制

• 批准号: 10192425
• 负责人: Corey Nicholas Miller
• 金额: $ 14.03万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10192425
• 关键词: Adult; Advisory Committees; Affect; Age; Aging; Antigens; Biological; Biology of Aging; Cell Compartmentation; Cell Survival; Cells; Cellular Immunity; Cellular biology; Climacteric; Clinical; Communicable Diseases; Communities; Data; Development; Development Plans; Doctor of Philosophy; Educational workshop; Elderly; Emigrant; Ensure; Environment; Epithelial; Flow Cytometry; Foundations; Frequencies; Functional disorder; Future; Goals; Growth; Hematopoietic; Heterogeneity; Homeostasis; Host Defense; Human; IL7 gene; ITGAM gene; ITGAX gene; Immune; Immunity; Immunofluorescence Immunologic; Immunology; Interleukin-13; Investigation; K-Series Research Career Programs; Licensing; Life; Link; Longevity; Mediator of activation protein; Mentors; Mentorship; Mesenchymal; Mesenchyme; Metabolic; Modeling; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Nature; Output; Pathway interactions; Peripheral; Production; Proteins; Publications; Research; Research Institute; Research Proposals; Residencies; Role; Shapes; Signal Transduction; Source; Stains; Stromal Cells; Structure of thymic medulla; System; T-Cell Development; T-Lymphocyte; Technical Expertise; Thymic epithelial cell; Thymocyte Development; Thymus Gland; Tissues; Training; Tumor Immunity; Tumor stage; Vaccination; Work; Youth; aged; arginase; base; career; career development; cytokine; emerging adult; eosinophil; epigenome; genome-wide; imprint; interest; interleukin-13 receptor; knowledge base; medical schools; mortality; mouse model; novel; polarized cell; post-doctoral training; programs; response; single-cell RNA sequencing; symposium; thymocyte; verdin photosensitizer; young adult

PROGRAM SUMMARY/ABSTRACT Poor T cell mediated immunity in the elderly is associated with increased morbidity and mortality from infectious diseases, suboptimal cancer immunity, and poor responses to vaccination. Waning T cell immunity is due in part to changes in thymic function beginning in the first decade of life and progressing to thymic involution in early to middle adulthood. However, how stromal-immune crosstalk maintains a differentiated, organized, and functional thymic stromal environment during early life, changes during thymic aging, and modifies naïve T cell character is poorly understood. Dr. Corey Miller’s career focus is to understand the mechanisms underlying medullary thymic function and dysfunction, including during aging, and how these states shape naïve T cell development, with the goal of informing novel immunorestorative therapies. His interest in stromal-immune crosstalk started during his doctoral research as an MD/PhD trainee, where he investigated peripheral sources of the T cell survival cytokine, IL-7. After completing medical school, he chose to forgo residency in favor of postdoctoral training and has focused on epithelial heterogeneity within the thymic medulla, leading to a first author publication in Nature. Dr. Miller’s pursuit of further career development training is based on his desire to leverage his expertise in stromal-immune crosstalk to transition towards a systems approach to understanding thymic homeostasis and naïve T cell development across life. This research proposal focuses on a surprising role for the thymic epithelium in expressing a hematopoietically-restricted cytokine to establish, polarize, and support the medullary stromal environment. Our preliminary data reveal the thymic epithelium as an unexpected source of IL-13. Using a mouse model in which IL-13 is selectively deleted from thymic epithelium, we propose aims to dissect its effects on epithelium and mesenchyme, myeloid cells, and, indirectly, naïve T cell character—thereby establishing a framework for understanding how changes in the medullary environment shape naïve T cell character. Dr. Miller has proposed a 5-year career development plan during which he will have direct mentorship by Dr. Mark Anderson and his advisory committee, which includes a carefully curated group of scientific leaders with expertise in T cell biology, type 2 cytokines, and aging biology. His proposed coursework, conference attendance and workshops will enable him to achieve new technical expertise and expand his knowledge base and scientific network in the field of aging biology. This training period will be spent at UCSF, which is an unrivaled institutional environment for basic immunology and scientific career development. In addition, proximity to the Buck Institute for Research on Aging and engagement of Buck CEO, Eric Verdin, as a mentor will ensure Dr. Miller’s scientific and professional growth within the aging biology community. At the completion of this career development award, Dr. Miller will have cultivated the technical skills and domain-specific expertise to launch an independent research program in thymic homeostasis and aging.

节目摘要/摘要 老年人T细胞介导的免疫功能低下与疾病发病率和死亡率的增加有关 传染病，癌症免疫力不佳，以及对疫苗接种反应差。T细胞免疫力减弱是 部分原因是胸腺功能的变化，从生命的第一个十年开始，并进展到胸腺 成年期早期至中期的退化。然而，基质免疫串扰如何保持差异化的、 早期生命中有组织的、有功能的胸腺基质环境，在胸腺老化过程中的变化，以及 改变幼稚的T细胞特性还知之甚少。科里·米勒博士的职业生涯重点是了解 髓质胸腺功能和功能障碍的潜在机制，包括在衰老期间，以及这些机制是如何 国家塑造了幼稚的T细胞发育，目的是为新的免疫修复疗法提供信息。 他对基质免疫相声的兴趣始于他作为医学博士/博士实习生的博士研究期间，在那里他 调查T细胞生存细胞因子IL-7的外周来源。在医学院毕业后，他选择了 放弃住院医师资格，转而接受博士后培训，并专注于 胸腺髓质，导致第一作者在《自然》上发表文章。米勒博士对进一步职业发展的追求 训练是基于他希望利用他在基质免疫相声方面的专业知识来过渡到 了解胸腺动态平衡和生命中幼稚T细胞发育的系统方法。 这项研究建议集中在胸腺上皮在表达一种令人惊讶的 限制造血的细胞因子来建立、极化和支持骨髓基质环境。 我们的初步数据显示，胸腺上皮是IL-13意想不到的来源。在中使用鼠标模型 其中IL-13被选择性地从胸腺上皮中删除，我们建议旨在剖析其对胸腺上皮细胞的影响 和间充质，髓系细胞，以及间接的幼稚T细胞特征-从而建立了一个框架 了解骨髓环境的变化如何塑造幼稚的T细胞特征。 米勒博士提出了一项为期5年的职业发展计划，在此期间，他将通过以下方式获得直接指导 马克·安德森博士和他的顾问委员会，其中包括一个精心策划的科学领袖小组 具有T细胞生物学、2型细胞因子和衰老生物学方面的专业知识。他提议的课程、会议 参加和参加研讨会将使他能够获得新的技术专长，并扩大他的知识库 和衰老生物学领域的科学网络。这段训练期将在加州大学旧金山分校度过，这是一个 为基础免疫学和科学事业发展提供无与伦比的制度环境。此外, 距离巴克老龄化研究所很近，巴克首席执行官埃里克·韦尔丁担任导师 将确保米勒博士在老龄化生物界的科学和专业发展。 在完成这一职业发展奖，米勒博士将培养技术技能和 在胸腺动态平衡和衰老方面启动独立研究计划的特定领域的专业知识。